Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with an estimated incidence of 10,000-15,000 new cases per year in the United States. Unlike AML, where karyotypic analysis is now the dominant molecular marker for outcome and clinical decision making, in CLL, karyotypic analysis is fraught with technical difficulties. This proposal attempts the characterization of novel genetic lesions as well as subtypes of known genetic lesions in CLL using unbiased genome-wide genomic profiling. CLL samples and paired normal buccal DNA samples for this study are from patients that are enrolled in a prospective translational research trial at the University of Michigan with planned serial specimen procurement for ten years and serial follow-up for twenty years. Analysis for loss of heterozygosity (LOH) and copy number changes is performed using the 50K SNP-chip platform developed by Affymetrix and software programs developed in the PI's laboratory and elsewhere. Upon characterization of regions of LOH, copy-neutral LOH or copy losses or gains, we will use uni- and multivariate analysis to determine the prognostic utility of individual lesions. Biological measurements to conduct the multivariate analysis, including assessment of the expression of ZAP70 by FACS and immunoglobulin variable gene mutation status, will be performed. This data will be supplemented, where needed, with targeted exon resequencing efforts of selected genes, such as p53. Ultimately, this data set will guide development or refinement of clinical risk-adapted trials in CLL, including experimental drug therapies and allogeneic stem cell transplantation. An additional benefit of the analysis of changes in the CLL genome is the delineation at high resolution of lesions that may harbor important genes in CLL biology and pathogenesis. [unreadable] [unreadable] Lay person abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an estimated incidence of 10,000-15,000 new cases per year in the United States. CLL remains incurable with chemotherapy alone and has a varied clinical course. An accurate risk assessment for individual patients using improved, unbiased genetic testing may prove helpful in recommending appropriate therapies, thereby increasing the possibility of improved patient outcome. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an estimated incidence of 10,000-15,000 new cases per year in the United States. CLL remains incurable with chemotherapy alone and has a varied clinical course. An accurate risk assessment for individual patients using unbiased genetic testing may prove helpful in recommending appropriate therapies including transplantation. [unreadable] [unreadable] [unreadable]